Wavelength-dispersive electron beam X-ray microanalysis was used to determine concentrations of aluminum, silicon and calcium in unfixed, unstained, postmorem human brain tissue. Analysis of over 20 senile (neuritic) plaques from 4 patients with Alzheimer's disease demonstrated that neither aluminum nor silicon is accumulated in senile plaques as compared to surrounding brain tissue. Values for these ions were low, at the limit of detection (10-20 ppm) and did not differ significantly from those of normal aged controls. Calcium, on the other hand, was slightly elevated in plaques, though the difference was <2 fold. Rates of entry of metals into the central nervous system were determined in unanesthetized rats following intravenous administration. Values differed among metal by at least three-orders of magnitude with manganese > lead > calcium = cadmium > gallium = iron. Calcium influx into cerebrospinal fluid is mediated primarily by a saturable, vitamin D- and parathyroid-independent mechanism at the choroid plexus epithelium. Manganese is transported by a high affinity carrier at the cerebral capillaries. The brain uptakes and deposition of aluminum, lead, cadmium and manganese, were enhanced by calcium deficiency, stressing the importance of diet in brain metal toxicity. Low dietary calcium also produced a precipitous drop (>90%) in serum copper and produced imbalances in other essential brain metals. The structural selectivity of the cerebrovascular large neutral amino acid carrier was characterized and the data used to obtain a drug showing improved brain delivery. The brain uptake of the putative exogenous neurotoxin, beta-N-methylamino-L-alanine, was shown to be mediated by the same carrier, as were two kynurenines that have been implicated as endogenous pathogens in brain disease.